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Abdelgalil AA, Monir R, Elmetwally M, Ghattas MH, Bazeed FB, Mesbah NM, Abo-Elmatty DM, Mehanna ET. The Relation of VEGFA, VEGFR2, VEGI, and HIF1A Genetic Variants and Their Serum Protein Levels with Breast Cancer in Egyptian Patients. Biochem Genet 2024; 62:547-573. [PMID: 37392242 DOI: 10.1007/s10528-023-10419-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 06/07/2023] [Indexed: 07/03/2023]
Abstract
Breast cancer is the most common type of cancer in Egyptian females. Polymorphisms in the angiogenesis pathway have been implicated previously in cancer risk and prognosis. The aim of the current study was to determine whether certain polymorphisms in the genes of vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), vascular endothelial growth inhibitor (VEGI), and hypoxia-inducible factor-1α (HIF1A) associated with breast cancer development. The study included 154 breast cancer patients and 132 apparently healthy age-matched females as a control group. VEGFA rs25648 genotyping was performed using (ARMS) PCR technique; while VEGFR2 rs2071559, VEGI rs6478106, and HIF-1α rs11549465 were genotyped by the PCR-RFLP method. Serum levels of VEGF, VEGFR2, VEGI, and HIF1A proteins in breast cancer patients and controls were measured by ELISA. There was a significant association between the VEGFA rs25648 C allele and breast cancer risk (OR 2.5, 95% CI 1.7-3.6, p < 0.001). VEGFA rs25648 C/C genotype was statistically significantly higher in breast cancer patients vs. control (p < 0.001). Participants with the T/T and T/C VEGFR2 rs2071559 genotypes had 5.46 and 5 higher odds, respectively, of having breast cancer than those with the C/C genotype. For the VEGI rs6478106 polymorphism, there was a higher proportion of C allele in breast cancer patients vs. control (p = 0.003). Moreover, the C/C genotype of VEGI rs6478106 was statistically significantly higher in breast cancer patients vs. control (p = 0.001). There was no significant difference in genotypes and allele frequencies of HIF1A rs11549465 polymorphism between breast cancer cases and control individuals (p > 0.05). Serum levels of VEGFA, VEGI, and HIF1A were considerably greater in women with breast cancer than in the control (p < 0.001). In conclusion, the genetic variants VEGFA rs25648, VEGFR2 rs2071559, and VEGI rs6478106 revealed a significant association with increased breast cancer risk in Egyptian patients.
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Affiliation(s)
- Amani A Abdelgalil
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt.
| | - Rehan Monir
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Medical Biochemistry, Faculty of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohamed Elmetwally
- Department of Surgical Oncology, Oncology Center, Mansoura University, Mansoura, Egypt
| | - Maivel H Ghattas
- Department of Medical Biochemistry, Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Fagr B Bazeed
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Noha M Mesbah
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Dina M Abo-Elmatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Eman T Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
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Kumar YS, Varghese S, Kulanthaivel L, Subbaraj GK. Association of VEGF polymorphisms and breast cancer susceptibility: Systemic review and meta-analysis. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Li Z, Wang Y, Liu C, Wang Z, Wang D, Liang X, Tian J. Association between VEGF single nucleotide polymorphism and breast cancer in the Northern China Han population. Breast Cancer Res Treat 2021; 186:149-156. [PMID: 33392836 DOI: 10.1007/s10549-020-06024-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/16/2020] [Indexed: 11/27/2022]
Abstract
PURPOSE To investigate the associations of four commonly studied single nucleotide polymorphisms (SNP) of the vascular endothelial growth factor (VEGF), including -460T/C (rs833061), - 634G/C (rs2010963), - 2578C/A (rs699947), and +936T/C (rs3025039), with the incidence, aggressiveness, and tumor markers expression of breast cancer in the Northern China Han population. METHODS Followed the genomic DNA extraction, a total of 259 patients with breast cancer (case group) and 273 healthy women (control group) underwent genotyping by PCR-LDR SNP assays. The associations between VEGF gene polymorphisms and the incidence, aggressiveness, and tumor markers expression of breast cancer were analyzed. RESULTS Significant differences were observed in allele frequency and genotype distribution of - 634G/C between breast cancer cases and healthy controls (p = 0.006, 0.013). Individuals who carry the G allele more likely had a lower risk of breast cancer (OR, 0.866, 95% CI 0.782-0.959). Compared with CC genotype carriers, women who had the CG and GG genotypes demonstrated a relatively lower risk (OR, 0.860, 95% CI 0.757-0.978, p = 0.022; OR, 0.778, 95% CI, 0.656-0.924, p = 0.004, respectively). When we stratified the group of patients according to the status of tumor markers, a significant association of - 634G/C SNP and Ki-67 expression was observed. The CC genotype carriers were more likely to be characterized by high expression of Ki-67 (p = 0.031). Further analysis showed that the - 460T/-634C/-2578C/+936C haplotype was more associated with a higher risk of breast cancer (OR, 1.445, 95% CI 1.123-1.859, p = 0.004), whereas the - 460T/- 634G/- 2578C/+936C one was associated with a lower risk (OR, 0.736, 95% CI 0.563-0.963, p = 0.025). CONCLUSIONS In the present study, we concluded that VEGF gene - 634G/C polymorphism is related to the incidence of breast cancer in the Han population in Northern China and also might be associated with tumor proliferation index Ki-67.
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Affiliation(s)
- Ziyao Li
- Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No 246 XueFu Road, Nan Gang Dist., Harbin, 150086, Heilongjiang Province, China
| | - Ying Wang
- Department of General Surgery, Second Hospital of Hebei Medical University, Add: 215 Peace Road, Shijiazhuang, Hebei Province, China
| | - Cong Liu
- Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No 246 XueFu Road, Nan Gang Dist., Harbin, 150086, Heilongjiang Province, China
| | - Zhenzhen Wang
- Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No 246 XueFu Road, Nan Gang Dist., Harbin, 150086, Heilongjiang Province, China
| | - Dongmo Wang
- Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No 246 XueFu Road, Nan Gang Dist., Harbin, 150086, Heilongjiang Province, China
| | - Xingyu Liang
- Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No 246 XueFu Road, Nan Gang Dist., Harbin, 150086, Heilongjiang Province, China
| | - Jiawei Tian
- Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No 246 XueFu Road, Nan Gang Dist., Harbin, 150086, Heilongjiang Province, China.
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Pharmacogenetic-Based Interactions between Nutraceuticals and Angiogenesis Inhibitors. Cells 2019; 8:cells8060522. [PMID: 31151284 PMCID: PMC6627675 DOI: 10.3390/cells8060522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/20/2019] [Accepted: 05/24/2019] [Indexed: 12/19/2022] Open
Abstract
Background: Angiogenesis inhibitors (AIs) have become established as an effective cancer treatment. Whereas their interactions with antineoplastic drugs have extensively been investigated, little is known of the effect of their co-administration with nutraceuticals/dietary supplements (N/DSs), which are often self-prescribed. N/DSs comprise a wide range of products such as herbs, nutrients, vitamins, minerals, and probiotics. Assessment of their interactions with cancer drugs, particularly AIs, is hampered by the difficulty of gauging the amount of active substances patients actually take. Moreover, there is no agreement on which approach should be used to determine which N/DSs are most likely to influence AI treatment efficacy. We present a comprehensive review of the metabolic routes of the major AIs and their possible interactions with N/DSs. Methods: The PubMed and Cochrane databases were searched for papers describing the metabolic routes of the main AIs and N/DSs. Results: Data from the 133 studies thus identified were used to compile a diagnostic table reporting known and expected AI-N/DS interactions based on their metabolization pathways. AIs and N/DSs sharing the cytochrome P450 pathway are at risk of negative interactions. Conclusions: Recent advances in pharmacogenetics offer exceptional opportunities to identify prognostic and predictive markers to enhance the efficacy of individualized AI treatments. The table provides a guide to genotyping patients who are due to receive AIs and is a promising tool to prevent occult AI-N/DS interactions in poor metabolizers. N/DS use by cancer patients receiving AIs is a topical problem requiring urgent attention from the scientific community.
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Vieira-Monteiro HDA, Freitas-Alves DR, Sobral-Leite M, Delou JMDA, Goulart-Citrangulo SMT, do Nascimento CT, E Castro TN, Koifman S, Perini JA, Vianna-Jorge R. Prognostic evaluation of VEGFA genotypes and haplotypes in a cohort of Brazilian women with non metastatic breast cancer. Cancer Biol Ther 2017; 17:674-83. [PMID: 27195611 DOI: 10.1080/15384047.2016.1190486] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Vascular Endothelial Growth Factor (VEGF) mediates angiogenesis, which is crucial for tumor development and progression. The present study aimed to evaluate the impact of VEGFA gene polymorphisms rs699947, rs833061, rs1570360, rs2010963 and rs3025039 on breast cancer features and prognosis. A cohort of Brazilian women (N = 1038) with unilateral non-metastatic breast cancer was evaluated. The association between VEGFA polymorphisms and histopathological features or pathological complete response (pCR) to neoadjuvant chemotherapy was evaluated by the Chi-square test, with calculation of the respective odds ratio (OR) and 95% confidence intervals (95% CI). The impact of individual categories on disease-free survival was evaluated using Kaplan-Meier curves and multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HRadjusted). Variant genotypes of rs699947 (CA + AA) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.82; 95% CI = 1.15 - 2.89), and with shorter disease-free survival among patients treated with neoadjuvant chemotherapy followed by mastectomy (HRadjusted = 1.82; 95% CI = 1.16 - 2.86). Variant genotypes of rs833061 (TC + CC) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.79; 95% CI = 1.12 - 2.84) and with positive lymph node status (OR = 1.34; 95% CI = 1.01 - 1.77), but showed no independent effect on disease-free survival. Variant haplotypes (*2 to *5) appear to favor pCR (OR = 7.1; 95% CI = 1.7 - 30.1). VEGFA genotyping may add to prognostic evaluation of breast cancer, with rs699947 being the most likely to contribute.
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Affiliation(s)
- Hayra de Andrade Vieira-Monteiro
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Daniely Regina Freitas-Alves
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Marcelo Sobral-Leite
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,c Division of Molecular Pathology, Netherlands Cancer Institute , Amsterdam , The Netherlands
| | - João Marcos de Azevedo Delou
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,d Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro , Rio de Janeiro , RJ , Brasil
| | | | | | - Thales Nascimento E Castro
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Sérgio Koifman
- b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Jamila Alessandra Perini
- b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil.,e Laboratório de Pesquisa de Ciências Farmacêuticas, Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste , Rio de Janeiro , RJ , Brasil
| | - Rosane Vianna-Jorge
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil.,d Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro , Rio de Janeiro , RJ , Brasil
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do Espírito Santo GF, Galera BB, Duarte EC, Chen ES, Azis L, Damazo AS, Saba GT, de Sousa Gehrke F, Guerreiro da Silva IDC, Waisberg J. Prognostic significance of vascular endothelial growth factor polymorphisms in colorectal cancer patients. World J Gastrointest Oncol 2017; 9:78-86. [PMID: 28255429 PMCID: PMC5314204 DOI: 10.4251/wjgo.v9.i2.78] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 09/02/2016] [Accepted: 12/14/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the associations of the genetic polymorphisms of vascular endothelial growth factor A (VEGF-A) -1498C>T and -634G>C, with the survival of patients with colorectal cancer (CRC).
METHODS A prospective cohort consisting of 131 Brazilians patients consecutively operated on with a curative intention as a result of sporadic colorectal carcinoma was studied. DNA was extracted from peripheral blood and its amplification and allelic discrimination for each genetic polymorphism was performed using the technique of polymerase chain reaction (PCR) in real-time. The real-time PCR technique was used to identify the VEGF-A -1498C>T (rs833031) and -634G>C (rs2010963) polymorphisms. Genotyping was validated for VEGF-A -1498C>T polymorphism in 129 patients and for VEGF-A -634G>C polymorphism in 118 patients. The analysis of association between categorical variables was performed using logistic regression, survival by Kaplan-Meier method and multivariate analysis by the Cox regression method.
RESULTS In the univariate analysis there was a significant association (OR = 0.32; P = 0.048) between genotype CC of the VEGF-A -1498C>T polymorphism and the presence of CRC liver metastasis. There was no association between VEGF-A -1498C>T polymorphism and VEGF-A -634G>C polymorphism with further clinical or anatomopathologic variables. The genotype CC of the VEGF-A -1498C>T polymorphism was significantly correlated with the 5-year survival (P = 0.032), but not significant difference (P = 0.27) was obtained with the VEGF-A -634G>C polymorphism with the 5-year survival in the univariate analysis. The genotype CT (HR = 2.79) and CC (HR = 4.67) of the polymorphism VEGF-A -1498C>T and the genotype CC (HR = 3.76) of the polymorphism VEGF-A -634C>G acted as an independent prognostic factor for the risk of death in CRC patients.
CONCLUSION The CT and CC genotypes of the VEGF-A -1498C>T and the CC genotype of the VEGF-A -634C>G polymorphisms are prognostic factors of survival in Brazilians patients with sporadic colorectal carcinoma.
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Choi SH, Ruggiero D, Sorice R, Song C, Nutile T, Vernon Smith A, Concas MP, Traglia M, Barbieri C, Ndiaye NC, Stathopoulou MG, Lagou V, Maestrale GB, Sala C, Debette S, Kovacs P, Lind L, Lamont J, Fitzgerald P, Tönjes A, Gudnason V, Toniolo D, Pirastu M, Bellenguez C, Vasan RS, Ingelsson E, Leutenegger AL, Johnson AD, DeStefano AL, Visvikis-Siest S, Seshadri S, Ciullo M. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies. PLoS Genet 2016; 12:e1005874. [PMID: 26910538 PMCID: PMC4766012 DOI: 10.1371/journal.pgen.1005874] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 01/26/2016] [Indexed: 12/31/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79x10-13), rs74506613 (JMJD1C, P = 1.17x10-19), rs4782371 (ZFPM1, P = 1.59x10-9) and rs2639990 (ZADH2, P = 1.72x10-8), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10-18; rs7043199, VLDLR-AS1, P = 5.12x10-14) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10-1467; rs1740073, C6orf223, P = 2.34x10-17; rs6993770, ZFPM2, P = 2.44x10-60; rs2375981, KCNV2, P = 1.48x10-100). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases. Vascular Endothelial Growth Factor (VEGF) is a protein with a fundamental role in development of vascular system. The protein, produced by many types of cells, is released in the blood. High levels of VEGF have been observed in different pathological conditions especially in cancer, cardiovascular, and inflammatory diseases. Therefore, identifying the genetic factors influencing VEGF levels is important for predicting and treating such pathologies. The number of genetic variants associated with VEGF levels has been limited. To identify new loci, we have performed a Genome Wide Association Study meta-analysis on a sample of more than 16,000 individuals from 10 cohorts, using a high-density genetic map. This analysis revealed 10 variants associated with VEGF circulating levels, 6 of these being novel associations. The 10 variants cumulatively explain more than 50% of the variability of VEGF serum levels. Our analyses have identified genes known to be involved in angiogenesis related diseases and genes implicated in platelet metabolism, suggesting the importance of links between this process and VEGF regulation. Overall, these data have improved our understanding of the genetic variation underlying circulating VEGF levels. This in turn could guide our response to the challenge posed by various VEGF-related pathologies.
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Affiliation(s)
- Seung Hoan Choi
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
- National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States of America
| | - Daniela Ruggiero
- Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy
| | - Rossella Sorice
- Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy
| | - Ci Song
- Population Sciences Branch, National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States of America
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Teresa Nutile
- Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy
| | - Albert Vernon Smith
- Icelandic Heart Association, Kopavogur, Iceland
- University of Iceland, Reykjavik, Iceland
| | - Maria Pina Concas
- Institute of Population Genetics, National Research Council of Italy, Sassari, Italy
| | - Michela Traglia
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
| | - Caterina Barbieri
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
| | - Ndeye Coumba Ndiaye
- UMR INSERM U1122, IGE-PCV “Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire”, Faculté de Pharmacie, Université de Lorraine, Nancy, France
| | - Maria G. Stathopoulou
- UMR INSERM U1122, IGE-PCV “Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire”, Faculté de Pharmacie, Université de Lorraine, Nancy, France
| | - Vasiliki Lagou
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | | - Cinzia Sala
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
| | - Stephanie Debette
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Department of Neurology, Bordeaux University Hospital, Bordeaux, France
- INSERM U897, Bordeaux, France
| | - Peter Kovacs
- University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - John Lamont
- Randox Laboratories, Crumlin, United Kingdom
| | | | - Anke Tönjes
- University of Leipzig, Department of Medicine, Leipzig, Germany
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- University of Iceland, Reykjavik, Iceland
| | - Daniela Toniolo
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
| | - Mario Pirastu
- Institute of Population Genetics, National Research Council of Italy, Sassari, Italy
| | - Celine Bellenguez
- Institut Pasteur de Lille, Lille, France
- INSEM U744, Lille, France
- Université Lille-Nord de France, Lille, France
| | - Ramachandran S. Vasan
- National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States of America
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, United States of America
| | - Erik Ingelsson
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Anne-Louise Leutenegger
- INSERM U946, Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, IUH, UMR-S 946, Paris, France
| | - Andrew D. Johnson
- Population Sciences Branch, National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States of America
| | - Anita L. DeStefano
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
- National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States of America
| | - Sophie Visvikis-Siest
- UMR INSERM U1122, IGE-PCV “Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire”, Faculté de Pharmacie, Université de Lorraine, Nancy, France
| | - Sudha Seshadri
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
- National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States of America
- * E-mail: (SS); (MC)
| | - Marina Ciullo
- Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy
- * E-mail: (SS); (MC)
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Ma J, Hu W, Zhang P, Sun Y, Wang N, Teng X, Qiao Q. The Association Between VEGF +936C/T and -634G/C Polymorphisms and Breast Cancer Susceptibility, Tumor Growth, and Metastases: Evidence From 20,728 Subjects. Cancer Invest 2015; 33:312-7. [PMID: 26067906 DOI: 10.3109/07357907.2015.1044664] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The relation between the polymorphisms of vascular endothelial growth factor (VEGF) and breast cancer remains inconclusive. In our meta-analysis based on 10,340 breast cancer patients and 10,388 controls, we found breast cancer susceptibility was elevated in individuals carrying the VEGF +936C allele, especially in Asians, and the +936CC increases tumor growth. The G allele of -634G/C polymorphism reduces breast cancer susceptibility in Asians, and breast cancer patients of -634GG genotype has decreased tumor growth. These results suggest that both the VEGF +936C/T and -634G/C polymorphisms influence breast cancer susceptibility and tumor growth, instead of metastasis.
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Affiliation(s)
- Jianguo Ma
- 1Department of Spine Surgery, PLA 425 Hospital , Sanya , China
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Langsenlehner U, Hofmann G, Renner W, Gerger A, Krenn-Pilko S, Thurner EM, Krippl P, Langsenlehner T. Association of vascular endothelial growth factor--a gene polymorphisms and haplotypes with breast cancer metastases. Acta Oncol 2015; 54:368-76. [PMID: 25152223 DOI: 10.3109/0284186x.2014.948056] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF-A) is a key regulator of tumor-induced angiogenesis and essential for tumor growth and distant tumor spread. The aim of the present study was to evaluate the role of VEGF-A polymorphisms and haplotypes for metastatic progression in breast cancer patients. MATERIAL AND METHODS We performed a prospective study including 801 breast cancer patients. Occurrence of metastases was examined in regular follow-up investigations. Seven VEGF-A polymorphisms were selected and determined by 5'-nuclease assays (TaqMan). The selection of VEGF-A variants was based upon their location (promoter or UTR) as well as a minor allele frequency of at least 0.10. Haplotypes and linkage disequilibrium were determined using the Haploview program. RESULTS Within a median follow-up time of 84 months, 165 (21%) patients developed distant metastases. In univariate analysis, carriers of the CCCCC haplotype formed by five polymorphisms upstream the coding region were at decreased risk of distant metastases [hazard ratio (HR)=0.743; 95% CI 0.579-0.953; p=0.019]. Univariate analysis also revealed a decreased risk of distant metastases for postmenopausal patients carrying the -634G>C polymorphism (HR 0.704; 95% CI 0.514-0.965; p=0.029) and the CCCCC haplotype (HR=0.645; 95% CI 0.464-0.898; p=0.009). After adjustment for other co-variates, the HR for distant metastases was 0.651 (95% CI 0.447-0.948) for postmenopausal carriers of the -634G>C polymorphism (p=0.025; corrected p-value=0.262), and 0.586 (95% CI 0.393-0.873) for postmenopausal patients with the CCCCC haplotype (p=0.009, corrected p-value=0.189). CONCLUSION The results from univariate and multivariate analyses suggest an influence of VEGF-A gene variants on the development of distant metastases in breast cancer patients. However, none of the observed associations reached statistical significance after correction for the effects of multiple testing. Additional prospective and sufficiently powered studies are essential before firm conclusions about the role of VEGF-A gene variants for distant progression in breast cancer can be drawn.
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Affiliation(s)
- Uwe Langsenlehner
- Division of Internal Medicine, GKK Outpatient Department , Graz , Austria
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10
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Kapahi R, Guleria K, Sambyal V, Manjari M, Sudan M, Uppal MS, Singh NR. Association of VEGF and VEGFR1 polymorphisms with breast cancer risk in North Indians. Tumour Biol 2015; 36:4223-34. [PMID: 25604142 DOI: 10.1007/s13277-015-3059-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 01/05/2015] [Indexed: 02/07/2023] Open
Abstract
The aim of present study was to evaluate the relationship between vascular endothelial growth factor (VEGF) -2578C/A, -2549I/D, -460T/C and -7C/T and VEGFR1 -710C/T polymorphisms with risk to breast cancer in North Indians. A total of 204 sporadic breast cancer patients and 204 controls were recruited for this case-control study. Significantly increased frequency of II genotype of -2549I/D polymorphism was observed in patients as compared to control individuals (odds ratio (OR) = 2.76, 95 % confidence interval (CI), 1.55-4.92; p = 0.0005). VEGF -2578AA genotype (OR = 2.87; 95 % CI, 1.61-5.10; p = 0.0003) and A allele (OR = 1.65, 95 % CI, 1.25-2.18; p = 0.0004) were found to be associated with increased risk for breast cancer. Individuals carrying CC genotype (OR = 2.23, 95 % CI, 1.25-3.97) and C allele (OR = 1.42, 95 % CI, 1.07-1.87) of VEGF -460T/C polymorphism were at higher risk of breast cancer. There was no significant difference in genotype and allele distribution of VEGF -7C/T and VEGFR1 -710C/T polymorphisms between cases and control individuals (p > 0.05). Linkage disequilibrium analysis showed a strong linkage between VEGF -2549I/D and -2578C/A polymorphisms (Lewontin's [Formula: see text] = 0.99; r (2) = 0.97), -2549I/D and -460T/C ([Formula: see text] = 0.94; r (2) = 0.84), and -2578C/A and -460T/C polymorphisms ([Formula: see text] = 0.93; r (2) = 0.83). In the present study, we concluded that VEGF -2549I/D, -2578C/A and -460T/C polymorphisms are associated with risk to breast cancer in Punjab, North India.
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Affiliation(s)
- Ruhi Kapahi
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, 143005, Punjab, India
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11
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Koutras A, Kotoula V, Fountzilas G. Prognostic and predictive role of vascular endothelial growth factor polymorphisms in breast cancer. Pharmacogenomics 2015; 16:79-94. [DOI: 10.2217/pgs.14.148] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Current evidence indicates that angiogenesis plays an important role in the pathogenesis of several malignancies, including breast cancer. The vascular endothelial growth factor (VEGF) pathway has been investigated extensively, due to its important role in angiogenesis. The major mediator of tumor angiogenesis is VEGF-A, frequently referred to as VEGF, which activates the VEGF receptor-2. The VEGF gene is located on chromosome 6 and constitutes a highly polymorphic gene. Numerous SNPs in the promoter, 5′- and 3′-untranslated regions (UTR) of VEGF gene have been recognized. This genetic variability possibly influences the production and function of VEGF. Subsequently, the VEGF SNPs may have an impact on breast cancer risk and disease outcome. Moreover, these SNPs may be of predictive value in patients receiving agents targeting the VEGF pathway. This review presents an update on the potential role of VEGF SNPs as prognostic and/or predictive markers in patients with breast cancer.
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Affiliation(s)
- Angelos Koutras
- Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Rion 26504, Greece
| | - Vasiliki Kotoula
- Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - George Fountzilas
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
- Department of Medical Oncology, ‘Papageorgiou’ Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
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Della-Morte D, Riondino S, Ferroni P, Palmirotta R, Pastore D, Lauro D, Guadagni F, Roselli M. Impact of VEGF gene polymorphisms in elderly cancer patients: clinical outcome and toxicity. Pharmacogenomics 2015; 16:61-78. [PMID: 25560471 DOI: 10.2217/pgs.14.136] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Vascular endothelial growth factors (VEGFs) are the key regulators in angiogenesis and have been shown to play a significant role in the progression and prognosis of angiogenesis-related diseases, such as cancer. VEGF inhibitors are a current pharmacological tumoral strategy. However, despite the strong association between aging and cancer incidence and progression, recent findings suggest impaired angiogenesis accompanied by a reduced expression of VEGF in cells derived from aging subjects. Specific variations of VEGF genes have been demonstrated to be genetic determinants for susceptibility, outcome and therapy response, especially for the solid tumors. Considering the complications present in frail elderly patients, analysis of VEGF genetic polymorphisms in these subjects may further help in tailoring an angiogenic pharmacological strategy, and in improving our ability to better understand prognosis during therapy-related to cancer.
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Affiliation(s)
- David Della-Morte
- Department of Systems Medicine, School of Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy
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Kapahi R, Manjari M, Sudan M, Uppal MS, Singh NR, Sambyal V, Guleria K. Association of +405C>G and +936C>T polymorphisms of the vascular endothelial growth factor gene with sporadic breast cancer in North Indians. Asian Pac J Cancer Prev 2014; 15:257-63. [PMID: 24528036 DOI: 10.7314/apjcp.2014.15.1.257] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF), an endothelial cell specific mitogen, has been implicated as a critical factor influencing tumor related angiogenesis. The aim of present study was to evaluate the relationship between VEGF +936C>T and +405C>G polymorphisms of VEGF with risk of breast cancer in Punjab, India. MATERIALS AND METHODS We screened DNA samples of 192 sporadic breast cancer patients and 192 unrelated healthy, gender and age matched control individuals for VEGF +936C>T and +405C>G polymorphisms using the PCR-RFLP method. RESULTS For the VEGF +405C>G polymorphism, we observed significantly increased frequency of GG genotype in cases as compared to controls and strong association of +405GG genotype was observed with three fold risk for breast cancer (OR=3.07; 95%CI 1.41-6.65; p=0.003). For the +936C>T polymorphism, significant associations of CT and combined CT+TT genotypes were observed with elevated risk of breast cancer (p=0.021; 0.023). The combined genotype combinations of GG-CC and GG- CT of +405C>G and +936C>T polymorphisms were found to be significantly associated with increased risk of breast cancer (p=0.04; 0.0064). CONCLUSIONS The findings of the present study indicated significant associations of VEGF +936C>T and +405C>G polymorphisms with increased breast cancer risk in patients from Punjab, North India.
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Affiliation(s)
- Ruhi Kapahi
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Punjab, India E-mail :
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14
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Rahoui J, Laraqui A, Sbitti Y, Touil N, Ibrahimi A, Ghrab B, Al Bouzidi A, Moussaoui Rahali D, Dehayni M, Ichou M, Zaoui F, Mrani S. Investigating the association of vascular endothelial growth factor polymorphisms with breast cancer: a Moroccan case–control study. Med Oncol 2014; 31:193. [DOI: 10.1007/s12032-014-0193-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 08/13/2014] [Indexed: 01/12/2023]
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15
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Vascular endothelial growth factor gene polymorphism (-634G/C) and breast cancer risk. Tumour Biol 2014; 35:7793-8. [PMID: 24816918 DOI: 10.1007/s13277-014-1997-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 04/22/2014] [Indexed: 10/25/2022] Open
Abstract
The aim of this meta-analysis was to assess if the -634G/C polymorphism represents a predisposition factor for the risk of breast cancer. We included eight published case-control studies, in which a total of 6,175 cancer cases and 6,421 cancer-free controls were included. Pooled ORs and 95 % CIs were calculated by the fixed effects model to evaluate the association of the -634G/C polymorphism and breast cancer risk. When all studies were pooled, we did not find statistical evidence of any significant association with overall breast cancer risk (ORBB vs. bb = 1.00, 95 % CI = 0.93-1.07, P = 0.999; ORBB + Bb vs. bb = 1.00, 95 % CI = 0.95-1.05, P = 0.999; ORBB vs. Bb + bb = 1.03, 95 % CI = 0.96-1.09, P = 0.984; ORallele B vs. allele b = 1.01, 95 % CI = 0.97-1.05, P = 0.998; ORBb vs. bb = 0.99, 95 % CI = 0.92-1.06, P = 0.992). In further stratified analyses by ethnicity and control source, no significant association was revealed. This study suggests that the -634G/C polymorphism does not appear to represent a risk factor for breast cancer.
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Luo T, Chen L, He P, Hu QC, Zhong XR, Sun Y, Yang YF, Tian TL, Zheng H. Vascular endothelial growth factor (VEGF) gene polymorphisms and breast cancer risk in a Chinese population. Asian Pac J Cancer Prev 2013; 14:2433-7. [PMID: 23725153 DOI: 10.7314/apjcp.2013.14.4.2433] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumours. Associations between three VEGF gene polymorphisms (-634 G/C, +936 C/T, and +1612 G/A) and breast cancer risk have been extensively studied, but the currently available results are inconclusive. Our aim was to investigate associations between three VEGF gene polymorphisms and breast cancer risk in Chinese Han patients. We performed a hospital-based case-control study including 680 female incident breast cancer patients and 680 female age-matched healthy control subjects. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect the three VEGF gene polymorphisms. We observed that women carriers of +936 TT genotypes [odds ratio (OR) =0.46, 95% confidence interval (CI) = 0.28, 0.76; P=0.002] or 936 T-allele (OR=0.81, 95% CI= 0.68, 0.98; P=0.03) had a protective effect concerning the disease. Our study suggested that the +1612G/A polymorphism was unlikely to be associated with breast cancer risk. The -634CC genotype was significantly associated with high tumor aggressiveness [large tumor size (OR=2.63, 95% CI=1.15, 6.02; P=0.02) and high histologic grade (OR=1.47, 95% CI= 1.06, 2.03; P=0.02)]. The genotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Our study revealed that the VEGF -634 G/C and +936 C/T gene polymorphisms may be associated with breast cancer in Chinese Han patients.
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Affiliation(s)
- Ting Luo
- Department of Head and Neck and Mammary Oncology, Cancer Center and State Key Laboratory of Biotherapy, Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University, Chengdu, China
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Slattery ML, John EM, Torres-Mejia G, Lundgreen A, Lewinger JP, Stern MC, Hines L, Baumgartner KB, Giuliano AR, Wolff RK. Angiogenesis genes, dietary oxidative balance and breast cancer risk and progression: the Breast Cancer Health Disparities Study. Int J Cancer 2013; 134:629-44. [PMID: 23832257 DOI: 10.1002/ijc.28377] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 06/24/2013] [Indexed: 01/12/2023]
Abstract
Angiogenesis is essential for tumor development and progression. Genetic variation in angiogenesis-related genes may influence breast carcinogenesis. We evaluated dietary factors associated with oxidative balance, DDIT4 (one SNP), FLT1 (35 SNPs), HIF1A (four SNPs), KDR (19 SNPs), MPO (one SNP), NOS2A (15 SNPs), TEK (40 SNPs) and VEGFA (eight SNPs) and breast cancer risk among Hispanic (2,111 cases and 2,597 controls) and non-Hispanic white (1,481 cases and 1,586 controls) women in the Breast Cancer Health Disparities Study. Adaptive rank truncated product (ARTP) analysis was used to determine gene and pathway significance with breast cancer. TEK was associated with breast cancer overall (pARTP = 0.03) and with breast cancer survival (pARTP = 0.01). KDR was of borderline significance overall (pARTP = 0.07), although significantly associated with breast cancer in both low and intermediate Native American (NA) ancestry groups (pARTP = 0.02) and estrogen receptor (ER)+/progesterone receptor (PR)- tumor phenotype (pARTP = 0.008). Both VEGFA and NOS2A were associated with ER-/PR- tumor phenotype (pARTP = 0.01 and pARTP = 0.04, respectively). FLT1 was associated with breast cancer survival among those with low NA ancestry (pARTP = 0.009). With respect to diet, having a higher dietary oxidative balance score (DOBS) was significantly associated with lower breast cancer risk [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.64-0.84], with the strongest associations observed for women with the highest NA ancestry (OR 0.44, 95% CI 0.30-0.65). We observed few interactions between DOBS and angiogenesis-related genes. Our data suggest that dietary factors and genetic variation in angiogenesis-related genes contribute to breast cancer carcinogenesis.
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SA-NGUANRAKSA DOONYAPAT, CHUANGSUWANICH TUENJAI, PONGPRUTTIPAN TAWATCHAI, KUMMALUE TANAWAN, ROJANANIN SUPAKORN, RATANAWICHHITRASIN ADUNE, PRASARTTONG-OSOTH PORAMAPORN, CHUTHATISITH SUEBWONG, PISARNTURAKIT PONGTHEP, AEUMRITHAICHAROENCHOK WARAPORN, RUSHATAMUKAYANUNT PRADIT, LOHSIRIWAT VISNU, BOONSRIPITAYANON MONGKOL, MALASIT PRIDA, O-CHAROENRAT PORNCHAI. Vascular endothelial growth factor −634G/C polymorphism is associated with increased breast cancer risk and aggressiveness. Mol Med Rep 2013; 8:1242-50. [DOI: 10.3892/mmr.2013.1607] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 07/24/2013] [Indexed: 11/05/2022] Open
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Kapahi R, Manjari M, Uppal MS, Singh NR, Sambyal V, Guleria K. Association of -2549 insertion/deletion polymorphism of vascular endothelial growth factor with breast cancer in North Indian patients. Genet Test Mol Biomarkers 2013; 17:242-8. [PMID: 23390884 DOI: 10.1089/gtmb.2012.0222] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AIMS The aim of the present study was to assess the role of the vascular endothelial growth factor (VEGF) -2549 insertion/deletion (I/D) polymorphism in susceptibility to sporadic breast cancer. METHODS DNA samples of 94 breast cancer patients and 94 unrelated healthy control individuals with matched age and gender from the same geographical region of Punjab, North West India were screened for the -2549 I/D polymorphism. Serum VEGF-C (sVEGF-C) levels of breast cancer patients and healthy controls were measured using an enzyme-linked immunosorbent assay. RESULTS The frequency of the II, ID, and DD genotype was 23.40 versus 10.64%, 48.94 versus 52.13%, and 27.66 versus 37.23%, in patients and controls, respectively. A statistically significant difference was observed for genotype distribution among the patients and controls (χ(2)=6.039, p=0.049). There was a significant increase in the I allele frequency in the patients as compared with controls (47.86 versus 36.70%, p=0.028). The sVEGF-C levels were also considerably higher in patients as compared to healthy controls (p<0.01). CONCLUSIONS The VEGF -2549 I/D polymorphism has a role in the susceptibility to breast cancer in the Amritsar region of Punjab, India.
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Affiliation(s)
- Ruhi Kapahi
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
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Sa-Nguanraksa D, O-Charoenrat P. The role of vascular endothelial growth factor a polymorphisms in breast cancer. Int J Mol Sci 2012. [PMID: 23203097 PMCID: PMC3509613 DOI: 10.3390/ijms131114845] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Breast cancer is the most common cancer in females and the leading cause of cancer death in women worldwide. Angiogenesis, the formation of new blood vessels, plays an important role in the development and progression of breast cancer. Vascular endothelial growth factor A (VEGFA), the key modulator of angiogenesis, is highly expressed in cancer tissue and correlates with its more aggressive features. Polymorphisms of VEGFA alter the levels of expression and subsequently influence the susceptibility and aggressiveness of breast cancer. Assessment of VEGFA polymorphisms may be used for the identification of patients suitable for anti-VEGFA therapy.
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Affiliation(s)
- Doonyapat Sa-Nguanraksa
- Division of Head-Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
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Five polymorphisms of vascular endothelial growth factor (VEGF) and risk of breast cancer: A meta-analysis involving 16,703 individuals. Cytokine 2011; 56:167-73. [DOI: 10.1016/j.cyto.2011.06.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 02/27/2011] [Accepted: 06/27/2011] [Indexed: 12/24/2022]
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Parmar S, Stingl JC, Huber-Wechselberger A, Kainz A, Renner W, Langsenlehner U, Krippl P, Brockmöller J, Haschke-Becher E. Impact of UGT2B7 His268Tyr polymorphism on the outcome of adjuvant epirubicin treatment in breast cancer. Breast Cancer Res 2011; 13:R57. [PMID: 21658222 PMCID: PMC3218946 DOI: 10.1186/bcr2894] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 04/15/2011] [Accepted: 06/09/2011] [Indexed: 01/18/2023] Open
Abstract
INTRODUCTION Epirubicin is a common adjuvant treatment for breast cancer. It is mainly eliminated after glucuronidation through uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7). The present study aimed to describe the impact of the UGT2B7(His268Tyr) polymorphism on invasive disease-free survival in breast cancer patients after epirubicin treatment. METHODS This is a pharmacogenetic study based on samples collected from 745 breast cancer patients of the Austrian Tumor of breast tissue: Incidence, Genetics, and Environmental Risk factors (TIGER) cohort who did not present metastases at baseline. This cohort included 205 women with epirubicin-based combination chemotherapy, 113 patients having received chemotherapy without epirubicin and 427 patients having received no chemotherapy at all. Of the epirubicin-treated subgroup, 120 were subsequently treated with tamoxifen. For all women UGT2B7(His268Tyr) was genotyped. Invasive disease-free survival was assessed using Kaplan-Meier and Cox's proportional hazard regression analysis. RESULTS Among the 205 epirubicin-treated patients, carriers of two UGT2B7(268Tyr) alleles had a mean invasive disease-free survival of 8.6 (95% confidence interval (CI) 7.9 to 9.3) years as compared to 7.5 (95% CI 6.9 to 8.0) years in carriers of at least one UGT2B7(268His) allele (adjusted hazard ratio (HR) = 2.64 (95% CI 1.22 to 5.71); P = 0.014). In addition, the impact of the UGT2B7(His268Tyr) polymorphism became even more pronounced in patients subsequently treated with tamoxifen (adjusted HR = 5.22 (95% CI 1.67 to 26.04); P = 0.015) whereas no such difference in invasive disease-free survival was observed in patients not receiving epirubicin. CONCLUSIONS Breast cancer patients carrying the UGT2B7(268Tyr/Tyr) genotype may benefit most from adjuvant epirubicin-based chemotherapy. These results warrant confirmation in further studies.
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Affiliation(s)
- Sumit Parmar
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Helmholtzstrasse 20, Ulm, 89081, Germany
| | - Julia Carolin Stingl
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Helmholtzstrasse 20, Ulm, 89081, Germany
| | - Ariana Huber-Wechselberger
- Institute of Medical and Laboratory Diagnostics, Elisabethinen Hospital Linz, Fadingerstrasse 1, Linz, 4020, Austria
| | - Alexander Kainz
- Department of Nephrology and Dialysis, Medical University Vienna, Währingergürtel 18-20, Vienna, 1090, Austria
| | - Wilfried Renner
- Clinical Institute of Medical and Laboratory Diagnostics, Medical University Graz, Auenbruggerplatz 15, Graz, 8036, Austria
| | - Uwe Langsenlehner
- Department of Internal Medicine, Hospital of Fürstenfeld, Krankenhausgasse 1, Fürstenfeld, 8280, Austria
| | - Peter Krippl
- Department of Internal Medicine, Hospital of Fürstenfeld, Krankenhausgasse 1, Fürstenfeld, 8280, Austria
| | - Jürgen Brockmöller
- Department of Clinical Pharmacology, University Göttingen, Robert-Koch-Strasse 40, Göttingen, 37075, Germany
| | - Elisabeth Haschke-Becher
- Institute of Medical and Laboratory Diagnostics, Elisabethinen Hospital Linz, Fadingerstrasse 1, Linz, 4020, Austria
- Christian Doppler Clinic, Private Paracelsus Medical University Salzburg, Ignaz Harrerstrasse 79, Salzburg, 5020, Austria
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Beeghly-Fadiel A, Shu XO, Lu W, Long J, Cai Q, Xiang YB, Zheng Y, Zhao Z, Gu K, Gao YT, Zheng W. Genetic variation in VEGF family genes and breast cancer risk: a report from the Shanghai Breast Cancer Genetics Study. Cancer Epidemiol Biomarkers Prev 2011; 20:33-41. [PMID: 21119072 PMCID: PMC3336364 DOI: 10.1158/1055-9965.epi-10-0793] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In addition to mediating aspects of physiologic and pathologic angiogenesis, the VEGF family also contributes to carcinogenesis. METHODS We comprehensively characterized genetic variation across four VEGF family genes and evaluated associations with breast cancer risk with odds ratios (OR) and 95% CIs for participants of the two-stage case-control Shanghai Breast Cancer Genetics Study (SBCGS). Stage 1 evaluated 200 single nucleotide polymorphisms (SNP) across two VEGF ligands (VEGFA and VEGFC) and two VEGF receptors (FLT1/VEGFR1 and KDR/VEGFR2) among 2,079 cases and 2,148 controls. Five SNPs with promising associations were assessed in stage 2 among 4,419 cases and 1,851 controls. RESULTS Two SNPs were consistently associated with breast cancer risk across our two study stages and were significant in combined analyses. Compared with FLT1 rs9551471 major allele homozygotes (AA), reduced risks were associated with AG (OR = 0.92, 95% CI: 0.84-1.00) and GG (OR = 0.78, 95% CI: 0.64-0.95) genotypes (P(trend) = 0.005). Compared with VEGFA rs833070 major allele carriers (CC or CT), increased risk was associated with TT genotypes (OR = 1.26, 95% CI: 1.05-1.52, P = 0.016). CONCLUSION Results from our study indicate that common genetic variation in VEGFA and FLT1 (VEGFR1) may contribute to breast cancer susceptibility. IMPACT Our findings provide clues for future studies on VEGF family genes in relation to cancer susceptibility and survival.
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Affiliation(s)
- Alicia Beeghly-Fadiel
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Wei Lu
- Shanghai Center for Disease Control and Prevention, Shanghai, China
| | - Jirong Long
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Yong-Bin Xiang
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai China
| | - Ying Zheng
- Shanghai Center for Disease Control and Prevention, Shanghai, China
| | - Zhongming Zhao
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Kai Gu
- Shanghai Center for Disease Control and Prevention, Shanghai, China
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai China
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
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24
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Stingl JC, Parmar S, Huber-Wechselberger A, Kainz A, Renner W, Seeringer A, Brockmöller J, Langsenlehner U, Krippl P, Haschke-Becher E. Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment. Curr Med Res Opin 2010; 26:2535-42. [PMID: 20849243 DOI: 10.1185/03007995.2010.518304] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The cytochrome P450 2D6 (CYP2D6) polymorphism was reported to have a significant impact on outcome of tamoxifen treatment in estrogen receptor positive breast cancer patients. The objective of this study was to explore the effect of the CYP2D6*4 polymorphism on tamoxifen treatment outcome in a cohort of patients from a single clinical trial which included women with a history of previous chemotherapy. RESEARCH DESIGN AND METHODS A total of 493 patients of the Austrian TIGER study receiving adjuvant tamoxifen therapy were studied for this pharmacogenetic interaction. All women with estrogen receptor positive tumors and tamoxifen therapy longer than 6 months were genotyped for CYP2D6*4 using TaqMan technology. Time to tumor progression, defined as local, regional, distant recurrence or contralateral breast cancer and progression free survival, was analyzed. RESULTS No significant difference in time to tumor progression or progression free survival between the CYP2D6*4 genotype groups in the overall study cohort was found. In a subgroup of patients treated with chemotherapy the CYP2D6*4 poor metabolizers had a tendency towards a shorter mean time to progression. In this group the mean time to tumor progression and the progression free survival were 1.0 years in the CYP2D6*4/*4 group, 6.3 years in the *1/*4 group and 4.97 years in the *1/*1 group (Wilcoxon p = 0.104). CONCLUSION While earlier data on CYP2D6 and tamoxifen excluded women with prior chemotherapy, the present analysis suggests that CYP2D6*4 genotype might be particularly crucial in this group of high-risk patients. Key limitations are restriction to the CYP2D6*4 allele and missing data of comedication.
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Affiliation(s)
- Julia Carolin Stingl
- Institute of Pharmacology of Natural Compounds and Clinical Pharmacology, University Ulm, Germany
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25
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Oliveira C, Lourenço GJ, Silva PMR, Cardoso-Filho C, Favarelli MHC, Gonçales NSL, Gurgel MSC, Lima CSP. Polymorphisms in the 5′- and 3′-untranslated region of the VEGF gene and sporadic breast cancer risk and clinicopathologic characteristics. Tumour Biol 2010; 32:295-300. [DOI: 10.1007/s13277-010-0121-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Accepted: 10/11/2010] [Indexed: 10/18/2022] Open
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26
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Li R, Zhao Y, Fan W, Chen H, Chen Y, Liu Y, Chen G, Zhou K, Huang F, Mao Y, Zhou L, Lu D, Shugart YY. Possible association between polymorphisms of human vascular endothelial growth factor A gene and susceptibility to glioma in a Chinese population. Int J Cancer 2010; 128:166-75. [DOI: 10.1002/ijc.25306] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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27
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Cao C, Fang JJ, Ying T, Sun SF, Lv D, Chen ZB, Ma HY, Yu YM, Ding QL, Shu LH, Deng ZC. Vascular Endothelial Growth Factor +936C/T and +405G/C Polymorphisms and Cancer Risk: a Meta-analysis. Arch Med Res 2010; 41:548-57. [DOI: 10.1016/j.arcmed.2010.09.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Accepted: 09/14/2010] [Indexed: 12/12/2022]
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28
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Chang CC, Hsieh YY, Lin WH, Lin CS. Leiomyoma and vascular endothelial growth factor gene polymorphisms: a systematic review. Taiwan J Obstet Gynecol 2010; 49:247-53. [PMID: 21056306 DOI: 10.1016/s1028-4559(10)60056-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2010] [Indexed: 01/19/2023] Open
Abstract
Leiomyomas (myoma or fibroid) are the most common gynecologic tumors that occur in women of reproductive age, but their molecular pathogenesis is still unknown. Since the growth of leiomyomas involve numerous vascular factors, an association between the leiomyoma and growth factors is suspected. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors. VEGF regulates angiogenesis and mediates sex steroid-induced cell growth and differentiation. VEGF-mediated activities seem to contribute to the pathogenesis of leiomyoma. Genetic variations, including polymorphisms, in VEGF might also be associated with the complex pathogenesis of leiomyomas. Here, we performed a systematic review of the roles of VEGF and its polymorphisms in the pathogenesis of leiomyoma.
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Affiliation(s)
- Chi-Chen Chang
- Department of Biological Science and Technology, National Chiao Tung University, Taichung, Taiwan
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29
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30
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Gu D, Wang M. VEGF 936C>T polymorphism and breast cancer risk: evidence from 5,729 cases and 5,868 controls. Breast Cancer Res Treat 2010; 125:489-93. [PMID: 20563637 DOI: 10.1007/s10549-010-0991-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Accepted: 06/11/2010] [Indexed: 11/25/2022]
Abstract
Vascular endothelial growth factor (VEGF) is one of the most potent endothelial cell mitogens and plays an important role in angiogenesis. Many published studies have evaluated the association between the VEGF 936C>T polymorphism and breast cancer risk. However, the published findings are inconsistent. In order to derive a more precise estimation of the association, a meta-analysis was performed in this study. A total of eight studies including 5,729 breast cancer cases and 5,868 controls were identified. Overall, no significant associations between the VEGF 936C>T polymorphism and breast cancer risk were found for TT versus CC (OR 0.93, 95% CI 0.73-1.19), CT versus CC (OR 0.91, 95% CI 0.77-1.09), TT/CT versus CC (OR 0.92, 95% CI 0.78-1.08), and TT versus CT/CC (OR 0.96, 95% CI 0.75-1.21). In the subgroup analysis by ethnicity, source of controls, and menopausal status, there was still no significant association detected in any of the genetic models. In summary, our results suggest that the VEGF 936C>T polymorphism may not contribute to breast cancer susceptibility.
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Affiliation(s)
- Dongying Gu
- Department of Molecular and Genetic Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 210029, People's Republic of China
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31
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Jain L, Vargo CA, Danesi R, Sissung TM, Price DK, Venzon D, Venitz J, Figg WD. The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors. Mol Cancer Ther 2009; 8:2496-508. [PMID: 19755511 DOI: 10.1158/1535-7163.mct-09-0302] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Angiogenesis is crucial for development and metastasis of tumors, and vascular endothelial growth factor (VEGF) is a key mediator of this process. The importance of VEGF in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. Inhibition of angiogenesis has shown promising clinical efficacy; however, not all patients treated with antiangiogenic agents derive benefit from them. Some patients are predisposed to refractory disease, whereas others develop resistance after initial response. Patients may also have different severity of drug-related adverse events. Optimization of drug administration based on disease status and individual responsiveness is important in limiting the treatment failure and minimization of side-effects. Single nucleotide polymorphisms (SNP) in VEGF may alter VEGF protein concentrations, influence the process of angiogenesis, and may relate to interindividual variation in the risk and progression of selected tumors, and their resistance to treatments. This review examines the role of SNPs in the VEGF gene as predictive and prognostic markers for major solid tumors, including the breast, non-small cell lung, colorectal, and prostate cancers. Selected VEGF SNPs seem to be associated with risk of these cancers; however, there is lack of unanimity in findings, in part influenced by differences in study design and analysis.
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Affiliation(s)
- Lokesh Jain
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, Maryland, USA
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32
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Chae YS, Kim JG, Sohn SK, Cho YY, Ahn BM, Moon JH, Jeon SW, Park JY, Lee IT, Choi GS, Jun SH. Association of vascular endothelial growth factor gene polymorphisms with susceptibility and clinicopathologic characteristics of colorectal cancer. J Korean Med Sci 2008; 23:421-7. [PMID: 18583877 PMCID: PMC2526538 DOI: 10.3346/jkms.2008.23.3.421] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Since vascular endothelial growth factor (VEGF) is known to be a potent pro-angiogenic factor, we evaluated the potential association of two VEGF gene polymorphisms (-634G>C and 936C>T) with the susceptibility and the clinicopathologic characteristics of colorectal cancer (CRC). The VEGF genotypes were determined using fresh colorectal tissue from 465 patients who had undergone a surgical resection and peripheral blood lymphocytes from 413 healthy controls by PCR/DHPLC assay. For the -634G>C polymorphism, the -634 GC or CC genotype was associated with a decreased risk of CRC (odds ratio [OR], 0.62; p=0.001) as a dominant model of C allele, whereas the 936 TT genotype correlated with advanced stage/ metastasis, a high serum level of CA19-9, and an higher grade in patients with CRC. In the haplotype analyses, haplotype -634C/936C and -634G/936T were associated with a decreased susceptibility of CRC (OR, 0.53 and 0.56; p<0.001, respectively). These observations imply that the VEGF gene polymorphisms may be associated with the susceptibility or clinicopathologic features of CRC. However, further studies of other VEGF sequence variants and their biological functions are needed to understand the role of the VEGF gene polymorphisms in the development and progression of CRC.
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Affiliation(s)
- Yee Soo Chae
- Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jong Gwang Kim
- Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Sang Kyun Sohn
- Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Yoon Young Cho
- Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Byung Min Ahn
- Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Joon Ho Moon
- Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Seoung Woo Jeon
- Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jae Yong Park
- Department of Biochemistry, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - In Taek Lee
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Gyu Seog Choi
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Soo-Han Jun
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
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Association of polymorphisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat 2008; 113:197-8. [PMID: 18210198 DOI: 10.1007/s10549-008-9902-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2007] [Accepted: 01/08/2008] [Indexed: 10/22/2022]
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Schneider BP, Radovich M, Sledge GW, Robarge JD, Li L, Storniolo AM, Lemler S, Nguyen AT, Hancock BA, Stout M, Skaar T, Flockhart DA. Association of polymorphisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat 2007; 111:157-63. [PMID: 17891484 DOI: 10.1007/s10549-007-9755-9] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2007] [Accepted: 09/06/2007] [Indexed: 10/22/2022]
Abstract
BACKGROUND Few studies have systematically explored a pathway approach: to test the association of multiple polymorphisms from multiple genes important to angiogenesis simultaneously with risk of breast cancer. We report our preliminary data evaluating the association of polymorphisms from seven genes known to influence angiogenesis with the likelihood of having breast cancer. METHODS We recruited 715 controls and 520 subjects with breast cancer. Subjects provided a blood specimen and completed a questionnaire that included common breast cancer risk factors and breast cancer status. We evaluated candidate polymorphisms in the following genes: Hypoxia Inducible Factor-1 alpha (HIF1alpha), Vascular Endothelial Growth Factor (VEGF), VEGF Receptor 1 (VEGFR-1), VEGFR-2, endothelial Nitric Oxide Synthase (eNOS), Neuropilin-1 (NRP-1) and Neuropilin-2 (NRP-2). Testing for associations between each polymorphism and the presence or absence of breast cancer was performed. RESULTS VEGF-2578 AA and -1498 CC genotypes were more common in cancer cases than controls (P = 0.06 and P = 0.04, respectively). These two genotypes remained significant predictors of breast cancer status after adjusting for non-genetic risk factors estimated by the Gail model (P = 0.03 and P = 0.03, respectively). When comparing women with invasive versus pre-invasive breast cancer, the eNOS-786 TT and eNOS 894 GG genotypes were associated with a greater likelihood of invasive disease and the eNOS 894 GG genotype was associated with a greater likelihood of having metastatic disease. CONCLUSION There is an association of the VEGF-2578A and -1498C alleles with increased breast cancer risk. This association remains significant when adjusted for Gail score-related risk factors.
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Affiliation(s)
- Bryan P Schneider
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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